A motivation-enhancing drug, also known as a pro-motivational drug, is a drug which increases motivation. Drugs enhancing motivation can be used in the treatment of motivational deficits, for instance in depression, schizophrenia, and attention deficit hyperactivity disorder (ADHD). They can also be used in the treatment of disorders of diminished motivation (DDMs), including apathy, abulia, and akinetic mutism, disorders that can be caused by conditions like stroke, traumatic brain injury (TBI), and neurodegenerative diseases. Motivation-enhancing drugs are used non-medically by healthy people to increase motivation and productivity as well, for instance in educational contexts. There is limited clinical data about medications for treating motivational deficits and disorders. In any case, drugs used for pro-motivational purposes are generally dopaminergic agents, for instance dopamine reuptake inhibitors (DRIs) like methylphenidate and modafinil, dopamine releasing agents (DRAs) like amphetamine, and other dopaminergic medications. Adenosine receptor antagonists, like caffeine and istradefylline, can also produce pro-motivational effects. Acetylcholinesterase inhibitors, like donepezil, have been used as well. Some drugs do not appear to increase motivation and can actually have anti-motivational effects. Examples of these drugs include selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (NRIs), and antipsychotics (which are dopamine receptor antagonists or partial agonists). Cannabinoids, for instance those found in cannabis, have also been associated with motivational deficits.
Dopaminergic agents Dopaminergic agents that have been found to produce pro-motivational effects in animals and/or humans include the following:
Dopamine reuptake inhibitors (DRIs) like bupropion, CE-123, CE-158, CT-005404, JJC8-088, JJC8-089, methylphenidate, (S)-MK-26, modafinil, MRZ-9547 ((R)-phenylpiracetam), nomifensine, PRX-14040, pyrovalerone, RDS03-94, and vanoxerine (GBR-12909) Dopamine releasing agents (DRAs) like amphetamine, methamphetamine, and lisdexamfetamine Dopamine D1 receptor agonists like SKF-81297 and PF-06412562 (CVL-562) Dopamine precursors like levodopa (L-DOPA) Catecholaminergic activity enhancers (CAEs) like selegiline (L-deprenyl), PPAP, and BPAP
Other dopaminergic agents Dopamine D2-like receptor agonists, including pramipexole, ropinirole, rotigotine, piribedil, bromocriptine, cabergoline, pergolide, and lisuride, have also been used to treat disorders of diminished motivation in humans. The clinical data on these agents for this use is very limited, but therapeutic successes have been reported. D2-like receptor agonists are known to have sedative-like and non-rewarding effects in humans. In any case, dopamine D2-like receptor antagonists, like haloperidol and other antipsychotics, are known to produce anti-motivational effects in animals and humans. Bromocriptine has been reported to improve anergia and motivation in humans in very limited clinical reports. On the other hand, pergolide failed to show pro-motivational effects in animals. Other dopaminergic drugs that have been used or suggested in the treatment of disorders of diminished motivation include rasagiline (a selective monoamine oxidase B (MAO-B) inhibitor; but see more below), tolcapone (a centrally-acting catechol-O-methyltransferase (COMT) inhibitor), and amantadine (an indirectly acting dopaminergic agent that acts via unknown mechanisms). Tolcapone, the only marketed COMT inhibitor that is centrally acting (as opposed to peripherally selective), shows antidepressant- and anti-anhedonia-like effects, stimulates exploratory behavior, and enhances the locomotor hyperactivity induced by psychostimulants like amphetamine and nomifensine in animals. Amantadine is widely used to treat multiple sclerosis-related fatigue, among other fatigue- and motivation-related disorders, and is recommended by the United Kingdom National Institute for Health and Care Excellence (NICE) guidelines for this use, though clinical data are limited. Although typical doses of dopamine D2 and D3 receptor antagonists reduce dopaminergic neurotransmission and produce anti-motivational effects, low doses of some of these drugs can preferentially block presynaptic dopamine D2 and D3 autoreceptors and thereby increase dopamine levels and enhance dopaminergic signaling. Examples of dopamine D2 and D3 receptor antagonists which have been used in this way include amisulpride, sulpiride, and ENX-104. At low doses resulting in dopamine D2 and D3 receptor occupancy levels of 10 to 50%, ENX-104 produced enhanced reward responsiveness, an anti-anhedonia-like effect, in rodents, whereas high doses achieving 65 to 80% occupancy resulted in antipsychotic-like effects, and further higher doses producing greater than 80% occupancy induced catalepsy. In addition to the preceding effects, ENX-104 has been found to augment amphetamine-induced dopamine release in rodents.
Mechanistic aspects of specific dopaminergic agents Dopamine levels and signaling in the nucleus accumbens, part of the ventral striatum and the mesolimbic reward pathway, are thought to play a key role in mediating behavioral activation and motivation. Dopamine releasing agents like dextroamphetamine are able to rapidly increase striatal dopamine levels by 700 to 1,500% of baseline in rodents. These drugs show greater magnitudes of impact on dopamine levels than do dopamine reuptake inhibitors like methylphenidate. In addition, whereas dopamine reuptake inhibitors show a clear dose–effect ceiling in their effects on dopamine levels, dopamine releasing agents do not and have been found to maximally increase dopamine levels by more than 5,000%. Atypical dopamine reuptake inhibitors like modafinil can also increase dopamine levels in the striatum and nucleus accumbens in animals, but have further reduced impacts on dopamine levels compared to psychostimulants like amphetamine and methylphenidate.
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